Fig. 6

Stage 4 ALS cerebellum demonstrated a distinct gene expression profile. (a) Heatmap of the 272 genes identified to be significantly different in stage 4 ALS patient cerebellum relative to stages 1–3. Gene counts are z-score normalised. (b) GO terms enriched among the genes upregulated and downregulated in stage 4 ALS patient cerebellum. The most representative member (lowest p-value) of each GO term cluster is displayed. Log₂ fold change indicates enrichment of member genes in differentially expressed genes versus all detected genes. (c) Cell-type deconvolution result using dtangle and cerebellum-derived single-nucleus RNA-seq (Tejwani et al., 2024). No cell type proportions were significantly different between ALS pTDP-43 pathology stage groups (Kruskal-Wallis rank sum test; significance threshold of p-value < 0.05). Controls were not included in statistical testing and are included here purely as a reference. (d) Venn diagram showing the number of proteins detected by SWATH-MS as differentially expressed in the cerebellum between each ALS pTDP-43 pathology stage group. Proteins defining each stage (i.e. the overlap of proteins identified as significantly up- or downregulated from each comparison) are indicated in boxes. Upregulated proteins are underlined while downregulated proteins appear in regular text. GC, granule cells; UBC, unipolar brush cells; PC, Purkinje cells; MLI1, molecular layer interneuron population 1; MLI2, molecular layer interneuron population 2; GoC, Golgi cells; AS, astrocytes; BG, Bergmann glia; OPC, oligodendrocyte progenitor cells; OL, oligodendrocytes; MG, microglia; END, endothelial cells